Genetics Core: Project Summary/Abstract Genetics Core C of the competing renewal of this Program Project Grant (PPG) entitled ?Frontotemporal Dementias: Genotypes and Phenotypes? aims to continue to build a large well-characterized cohort of DNA samples, and use and share these samples for cutting-edge genomic applications to foster new genetic discoveries within and beyond this PPG, which seeks to advance understanding of mechanisms underlying the onset and progression of hereditary and sporadic forms of frontotemporal degeneration (FTD). FTD manifests clinically with progressive behavioral and/or language deficits with subtypes classified neuropathologically by the different disease proteins found as cellular inclusion bodies, of which the most common are TAR DNA binding protein (TDP-43, FTLD-TDP) and tau (FTLD-tau). Autosomal dominant forms of FTD have been identified with mutations most commonly in MAPT, GRN, and C9orf72, and each is associated with a specific FTLD pathological subtype, for example, GRN and C9orf72 mutations with FTLD-TDP and MAPT mutations with FTLD-tau. In addition, genetic risk factors, such as TMEM106B, have been identified. Studying the genetics of FTD can help to elucidate its etiology and pathophysiology as well as identify genetic factors that increase risk for disease or modify its phenotype. New evidence for protein aggregation and spread throughout the CNS in FTD and other NDs (studied in Projects 3 and 4) provides a promising target for therapeutic development for these currently incurable disorders. However, accurate, as well as rapid, ante mortem diagnosis of FTD underlying pathology is crucial for this effort. A personalized medicine approach that combines genetic information with other biomarkers (imaging, biofluids) to better define FTD clinical endophenotypes will enhance power for clinical trials focused on slowing or preventing progression of spread of tau, TDP-43 and other FTLD-associated pathologies. To enable genetic studies of FTD in this PPG, Core C will collect and bank DNA from Clinical Core B subjects and autopsy brains characterized in Neuropathology and Biomarker Core D. DNA will be used for genetic analysis by Core C and Project 2 and be available to share with other collaborators. Genetic mutations and SNP risk factor data, will be used by Project 1 to assess factors contributing to rate of disease progression. Genotype data will enable selection of cases (either inclusion or exclusion of cases with a mutation, for example) for study in Projects 1-4. In addition, genetic data will enable clinical, pathologic and genetic correlations with data from Projects 1-4 and Cores B and D. Biostatistics and Data Management Core E will perform statistical analysis for these studies. Genomic analysis at the exome and genome level will be used to identify new genes in families without an identified mutation and for additional genomic association studies both within this PPG and in local, national, and international collaborations under the guidance of Administrative Core A.